Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
Shokichi Takahama1, Kazuya Ishige2, Takuto Nogimori1
1Laboratory of Immunosenescence, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki City, Osaka 567-0085, Japan.
Abstract:
Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3',5')pA (3',5'p] (3'-3'-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques. Both ligands induced transient local and systemic inflammatory responses and systemic immunomodulatory responses, including the upregulation of interferon-α (IFN-α) and IFN-γ expression and the activation of multiple immunocompetent cell subsets. Better immunological responses were observed in animals that received c-di-AMP compared with those that received 3'-3'-cGAMP. Multi-parameter analysis using a dataset obtained before administering the ligands predicted the efficacy outcome partially. Importantly, the efficacy of these ligands was reduced in older macaques. We propose that 0.5 mg/kg c-di-AMP via intramuscular administration should be the optimal starting point for clinical studies. Our study is the first to demonstrate the age-dependent safety and efficacy of STING-L in non-human primates and supports the potential of STING-L use as a direct immunomodulator in vivo.
Insights
Stimulator of interferon genes ligand (STING-L) therapy shows promise for cancer treatment. This study in macaques found cyclic-di-adenosine monophosphate (c-di-AMP) to be safe and effective, with efficacy dependent on age.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Stimulator of interferon genes (STING) ligands are novel immunomodulatory agents for cancer therapy.
- Previous STING ligand (STING-L) studies were limited to mouse models, lacking non-human primate safety and efficacy data.
Purpose of the Study:
- To evaluate the safety and immunomodulatory effects of STING ligands, cyclic-di-adenosine monophosphate (c-di-AMP) and 3'-3'-cGAMP, in cynomolgus macaques.
- To determine the optimal dose and administration route for STING-L in non-human primates for future clinical translation.
Main Methods:
- Administered escalating doses of c-di-AMP and 3'-3'-cGAMP via intramuscular and intravenous routes to macaques.
- Monitored local and systemic inflammatory responses, immunomodulatory effects (e.g., interferon expression), and immunocompetent cell activation.
- Analyzed age-dependent efficacy and utilized pre-treatment data to predict outcomes.
Main Results:
- Both STING ligands induced transient inflammatory responses and systemic immunomodulation, including increased interferon-α and IFN-γ.
- c-di-AMP demonstrated superior immunological responses compared to 3'-3'-cGAMP.
- STING-L efficacy was diminished in older macaques, indicating an age-dependent effect.
Conclusions:
- 0.5 mg/kg c-di-AMP via intramuscular administration is proposed as the optimal starting dose for clinical trials.
- This study is the first to report age-dependent safety and efficacy of STING-L in non-human primates.
- STING-L holds significant potential as a direct in vivo immunomodulator for cancer treatment.
More Related Videos
12:21A Mouse Model for the Transition of Streptococcus pneumoniae from Colonizer to Pathogen upon Viral Co-Infection Recapitulates Age-Exacerbated Illness
Published on: September 28, 2022
06:25Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining
Published on: December 23, 2016